Search Results (8,799)

Background/Objective: Avapritinib is an orally bioavailable tyrosine kinase inhibitor and was approved by the FDA in 2020 for gastrointestinal stromal tumor treatments. Although avapritinib is known to be chiral, its stereochemistry was initially established randomly. This study aims to develop a definitive method for determining avapritinib’s absolute configuration and propose a universal methodology for stereochemical characterization of flexible chiral drugs. Methods: The absolute configuration of avapritinib was determined through an integrated approach combining chiral resolution, chiroptical spectroscopy and synthetic validation. Enantiomeric separation was achieved via chiral liquid chromatography, followed by comprehensive chiroptical characterization including electronic circular dichroism (ECD), specific optical rotation and optical rotatory dispersion. Conformational analysis and density functional theory (DFT) calculations correlated experimental spectra with theoretical predictions, facilitating definitive configurational assignment. The stereochemical determination were further verified through ECD derivatization and chemical synthesis. Finally, the enantiomers’ kinase inhibition profiles against c-KIT D816V were quantitatively assessed. Results: Two enantiomers of avapritinib were resolved via chiral HPLC and a Chiralpak IG column. Through combined experimental ECD spectra and time-dependent DFT calculations employing the core extraction method, the levo-isomer was unambiguously determined as S configuration. This stereochemical assignment was confirmed by p-cyanobenzaldehyde derivatization and de novo synthesis. Biological evaluation revealed (S)-(−)-avapritinib exhibited superior c-KIT D816V inhibitory activity compared to its (R)-(+)-counterpart, a finding corroborated by molecular docking studies elucidating their differential target interactions. Conclusions: This study advances avapritinib stereochemical understanding and establishes a definitive protocol for its absolute configuration assignment, serving as a paradigm for flexible chiral drug characterization. Full article

The management of power supply and distribution is becoming increasingly challenging because of the significant increase in energy demand brought on by global population growth. Buildings are estimated to be accountable for 40% of the worldwide use of energy, which underlines how important accurate demand estimation is for the design and construction of electrical infrastructure. In this respect, transmission and distribution network planning must be adjusted to ensure a smooth transition to the National Interconnected System (NIS). A technical and analytical scientific approach to a modern neighbourhood in Ecuador called “the Nuevo Samborondón” case study (NSCS) is laid out in this article. Collecting geo-referenced data, evaluating the current electrical infrastructure, and forecasting energy demand constitute the first stages in this research procedure. The sector’s energy behaviour is accurately modelled using advanced programs such as 3D design software for modelling and drawing urban architecture along with a whole building energy simulation program and geographical information systems (GIS). For the purpose of recreating several operational situations and building the distribution infrastructure while giving priority to the current urban planning, an electrical system model is subsequently developed using power system analysis software at both levels of transmission and distribution. Furthermore, seamless digital substations are suggested as a component of the nation’s electrical infrastructure upgrade to provide redundancy and zero downtime. According to our findings, installing a 69 kV ring is a crucial step in electrifying NSCS and aligning electrical network innovations with urban planning. The system’s capacity to adjust and optimize power distribution would be strengthened provided the algorithms were given the freedom to react dynamically to changes or disruptions brought about by distributed generation sources. Full article

Extensive research has been conducted on the catalytic properties of molybdenum disulfide (MoS₂) materials in the context of the hydrogen evolution reaction (HER). This study focuses on exploring hybrid MoS₂/Au structures as a catalyst for HER, utilizing linear sweep voltammetry as the experimental methodology. Firstly, 2D-MoS₂ flakes were synthesized by the chemical vapor deposition (CVD) approach and directly added to gold nanoparticles during or after their preparation process. The prepared nanocomposites were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Raman spectroscopy, and scanning electron microscopy with energy-dispersive X-ray analysis (SEM/EDX). The HER performance was tested for the two resulting samples to show that the preparation of gold nanoparticles with the coexistence of CVD-MoS₂ flakes produces a superior electrocatalytic performance of the sample in a neutral medium. Notably, the onset potential was measured as −0.152 V (versus reversible hydrogen electrode (RHE)) with an exchange current density (j₀) of 0.22 mA/cm². Chronoamperometric data show that all composites retained initial current densities for 15 hours, confirming stable, efficient HER performance post-decay. Full article

This article presents a low-noise amplifier (LNA) with high image rejection ratio (IRR) operating in the 5G millimeter-wave band using a 65 nm CMOS process. The circuit adopts an inter-stage notch filtering structure composed of a transformer and a switched capacitor array to achieve image suppression and impedance matching with no die area overhead. By adjusting the values of the switch capacitor array, the transmission zeros are positioned in the stopband while the poles are placed in the passband, thereby realizing image rejection. Furthermore, the number and distribution of poles under the both real and complex impedance conditions are analyzed. Moreover, the quality factor (Q) of the zero is derived to establish the relationship between Q and the image rejection ratio, guiding the optimization of both gain and IRR of the circuit design. Measurement results demonstrate that the LNA exhibits a gain of 18 dB and a noise figure (NF) of 4.4 dB at 40 GHz, with a corresponding IRR of 53.4 dB when the intermediate frequency (IF) is 6 GHz. The circuit demonstrates a 3 dB bandwidth from 36.3 to 40.7 GHz, with an IRR greater than 42 dB across this frequency range. The power consumption is 25.4 mW from a 1 V supply, and the pad-excluded core area of the entire chip is 0.13 mm². Full article

Woven composites and natural fiber-reinforced composites both have widespread applications in various industries due to their appealing load-carrying capacity and performance compared to conventionally manufactured composites, such as polymeric composites. Representative volume element (RVE) generation is one of the most effective and widely adopted methods for estimating mechanical performance in current research. This study aims to explore the effects of three significant factors in woven composite RVEs: yarn spacing (from 0.5 mm to 1.5 mm), fabric thickness (from 0.2 to 0.5 mm), and shear angle (from 3.5 to 15 degrees) through finite element methods and statistical analysis to understand their effectiveness in the elastic moduli’s. The validation of this research has been conducted using available literature. The generation of representative volume elements (RVEs) and the calculation of elastic moduli were performed using ANSYS-19, including the material designer feature. The experimental design was carried out using Design-Expert software version 13, which used response surface methodology. The materials selected for this study were jute fiber and epoxy. After obtaining the elastic moduli from the ANSYS material designer, three responses were considered: longitudinal Young’s modulus (E₁₁), in-plane shear modulus (G₁₂), and major Poisson’s ratio (V₁₂). ANOVA (Analysis of Variance) and 3D contour graphs were generated to further analyze and correlate the effects of the selected materials on these responses. These investigations revealed that in comparison to twill structure, plain structure in natural fiber-reinforced woven composites could be a good alternative. Additionally, the findings highlighted that yarn spacing and fabric thickness significantly influence the considered moduli in plain-weave NFRC material RVEs. However, in twill-woven composite RVEs, the effects of yarn spacing, fabric thickness, and shear angle were found to be considerable. Moreover, statistical analysis has found the best combinations for both plain and twill structures, while the yarn spacing was 1 mm, the shear angle was 9.25 degrees, and the fabric thickness was 0.35 mm. Full article

Understanding the molecular regulation of citric acid accumulation in citrus fruits is crucial, as acidity directly influences fruit flavor, consumer preference, and commercial value. Citric acid is the predominant organic acid in citrus, and its levels are shaped by several factors, including genetic and developmental factors. ‘Jinyan’ Bingtang orange (Citrus sinensis cv. Jinyan) is a novel mutant derived from ‘Jinhong’ Bingtang orange (C. sinensis cv. Jinhong) that has a noticeably sour taste. However, the molecular basis of the increased citrate content in ‘Jinyan’ fruits remains unclear. This study compared the organic acid profiles and expression of citric acid metabolism-related genes between ‘Jinyan’ and ‘Jinhong’ fruit juice sacs throughout fruit development. The trend of citric acid content in both cultivars was similar; however, ‘Jinyan’ consistently presented significantly higher levels than ‘Jinhong’ did from 95 to 215 days after flowering (DAF). After 155 DAF, the transcript levels of citrate biosynthesis-related genes (PEPC1, PEPC2, PEPC3, CS1, and CS2) and citrate transport-related genes (V₁-E1, V₁-E2, V₀-a2, V₀-d, VHP1, VHP2, and CsPH8) were significantly greater in ‘Jinyan’ than in ‘Jinhong’. In contrast, citrate degradation-related genes (NAD-IDH2 and NAD-IDH3) were expressed at lower levels than in ‘Jinhong’. Notably, the expression patterns of V₁-E2 and CsPH8 closely matched the changes in citrate content in both cultivars. These results indicate that, compared with ‘Jinhong’, high citric acid accumulation in the juice sacs of ‘Jinyan’ fruit is likely due to increased citrate synthesis (via upregulated PEPCs and CSs) and increased vacuolar citrate sequestration (via upregulated proton pumps and transporters), coupled with reduced citrate degradation (lower NAD-IDH2/3). Full article

The integration of computer vision and deep learning into Building Information Modeling (BIM) workflows has created a growing need for structured datasets that enable the semantic segmentation of indoor building elements. This paper presents StructScan3D v1, the first version of an RGB-D dataset specifically designed to facilitate the automated segmentation and modeling of architectural and structural components. Captured using the Kinect Azure sensor, StructScan3D v1 comprises 2594 annotated frames from diverse indoor environments, including residential and office spaces. The dataset focuses on six key building elements: walls, floors, ceilings, windows, doors, and miscellaneous objects. To establish a benchmark for indoor RGB-D semantic segmentation, we evaluate D-Former, a transformer-based model that leverages self-attention mechanisms for enhanced spatial understanding. Additionally, we compare its performance against state-of-the-art models such as Gemini and TokenFusion, providing a comprehensive analysis of segmentation accuracy. Experimental results show that D-Former achieves a mean Intersection over Union (mIoU) of 67.5%, demonstrating strong segmentation capabilities despite challenges like occlusions and depth variations. As an evolving dataset, StructScan3D v1 lays the foundation for future expansions, including increased scene diversity and refined annotations. By bridging the gap between deep learning-driven segmentation and real-world BIM applications, this dataset provides researchers and practitioners with a valuable resource for advancing indoor scene reconstruction, robotics, and augmented reality. Full article

The phenomena of regio- and stereoselectivity and the molecular mechanism of the [2 + 2] cycloaddition reaction between (E)-2-arylnitroethenes and the ynamine molecular system were analyzed using wb97xd/6-311 + G(d) (PCM) quantumchemical calculations. It was found that, independently of the stepwise nature of the cycloaddition, the full retention of the stereoconfiguration of the nitroalkene can be interpreted and explained. Next, the analysis of the electronic properties of the localized reaction intermediate suggests its possible zwitterionic nature. Additionally, the solvent and the substituent effect on the reaction course were also evaluated. In consequence, the proposed mechanism can be treated as general for some groups of [2 + 2] cycloaddition processes. Lastly, for the model process, the full Bonding Evolution Theory (BET) analysis along the reaction coordinate was performed. It was found that the [2 + 2] cycloaddition reaction between (E)-2-phenylonitroethene and ynamine begins with the formation of two pseudoradical centers at the C2 and C3 atoms. First, a C2-C3 single bond is formed in phase V by combining two pseudoradical centers, while the formation of a second C4-C1 single bond begins at the last, eleventh phase of the reaction path. A BET analysis of intermediate (I) allows it to be classified as a compound with a pseudoradical structure. Next to zwitterions and biradicals, it is evidently new type of intermediate on the path of the [2 + 2] cycloaddition reaction. Full article

The aim of this study was to investigate the effect of Ostwald ripening inhibitors on D-limonene (D-LMN) nanoemulsions and to elucidate their impact on oral cancer cells. Various inhibitors, including olive oil, soybean oil, and perilla oil, were incorporated into D-LMN nanoemulsions at different ratios (25:75–75:25, D-LMN to inhibitor). The resulting nanoemulsions were evaluated for droplet size, size distribution, zeta potential, stability, droplet morphology, cytotoxicity, antimetastatic and anti-invasive activities, apoptosis induction, and cell cycle arrest. Results showed that the 75:25 D-LMN to inhibitor ratio produced the smallest droplet size and exhibited great stability, particularly with perilla oil. Notably, D-LMN nanoemulsions displayed strong anti-oral cancer effects by reducing cell viability, metastasis, and invasion. Apoptosis was induced, as evidenced by nuclear fragmentation, Annexin V binding, and altered expression of BAX, BCL-XL, Cytochrome c, and Caspase-9. Additionally, the nanoemulsions caused cell cycle arrest via downregulation of Cyclin D1, CDK2, CDK4, and CDK6. These findings highlight the potential of D-LMN nanoemulsions as a promising alternative therapeutic strategy for oral cancer treatment. Full article

Wastewater-based epidemiology (WBE) offers valuable insight into viral circulation at the community level. In this study, we combined digital PCR (dPCR) with molecular typing to investigate the prevalence and diversity of human adenoviruses (HAdVs) in untreated wastewater samples collected throughout Italy. HAdV genomes were detected in over 93% of the 168 samples analyzed, with concentrations up to 4.5 × 10⁶ genome copies per liter. For genotypic characterization, we used nested PCR followed by Sanger and Oxford Nanopore Technologies (ONTs) long-read sequencing. While Sanger sequencing identified three dominant genotypes (HAdV-A12, HAdV-B3, and HAdV-F41), ONT sequencing provided enhanced resolution, confirming all previously identified types and revealing seven additional genotypes: HAdV-B21, HAdV-C5, HAdV-D45, HAdV-D46, HAdV-D49, HAdV-D83, and HAdV-F40. This comprehensive approach highlights the added value of ONT long-read sequencing in uncovering the genetic complexity of adenoviruses in wastewater, particularly in detecting rare or low abundance types that conventional methods may miss. Our findings highlight the value of integrating quantitative and high-resolution molecular tools in WBE to improve surveillance and better understand the epidemiology of viral pathogens circulating in the human population. Full article

Terahertz (THz) antennas are among the critical components required for enabling the transition to sixth-generation (6G) wireless networks. Although research on THz antennas for 6G communication systems has garnered significant attention, a standardized antenna design has yet to be established. This study introduces the modeling of a full-metal transverse slotted waveguide antenna (TSWA) for 6G and beyond. The proposed antenna operates across the upper regions of the V-band and the entire W-band. Designed and simulated using widely adopted full-wave analysis tools, the antenna achieves a peak gain of 17 dBi and a total efficiency exceeding 90% within the band. Additionally, it exhibits pattern-reconfigurable capabilities, enabling main lobe beam steering between $5^{\circ }$ and 68° with low side lobe levels. Simulations are conducted to assess the power handling capability (PHC) of the antenna, including both the peak (PPHC) and average (APHC) values. The results indicate that the antenna can handle 17 W of APHC within the W-band and 3.4 W across the 60–160 GHz range. Furthermore, corona discharge and multipaction analyses are performed to evaluate the antenna’s power handling performance under extreme operating conditions. These features make the proposed TSWA a strong candidate for high-performance space applications, 6G communication systems, and beyond. Full article

The purpose of this study was to investigate polymorphic variants of the genes FGB (rs1800790), NOS3 (rs2070744) and TMPRSS2 (rs12329760) in patients with SARS-CoV-2 and to determine their role in the COVID-19 severity course against the background of antiviral therapy. Real-time polymerase chain reaction (RT-PCR) was used to genotype the polymorphism of the selected genes. GS-5734 (remdesivir) was prescribed as the basic antiviral drug. Binary logistic regression confirmed a low probability of COVID-19 developing in carriers of the A-allele of the FGB gene. The highest probability of moderate and severe COVID-19 clinical forms developing was found in G-allele carriers (especially the GG genotype) of the FGB gene (rs1800790) and the T-allele of the TMPRSS2 gene (rs12329760). Antiviral drug GS-5734 (remdesivir) administration with anti-inflammatory therapy reduces the TMPRSS2 blood level in moderate COVID-19, IL-6 in severe COVID-19 course, and fibrinogen A- and D-dimers in both groups. The proposed treatment does not significantly affect the concentration of endothelin-1, but a decrease in procalcitonin associated with additional antibacterial use was observed, especially in severe COVID-19. Full article

Objectives: This study characterised and evaluated the stability, solubility, and in vitro drug release of OA- and AA-loaded SLNs. Methods: The OA- and AA-SLNs were formulated using the emulsion solvent evaporation method and characterised based on particle size (PS), polydispersity index (PDI), zeta potential (ZP), and transmission electron microscopy (TEM). Solubility studies were conducted in PBS (pH 1.2 and 6.8) and dH₂O using HPLC, while in vitro drug release was assessed in simulated intestinal fluid (SIF) (pH 6.8). Results: The optimised OA-SLNs (1:1 drug-to-lipid ratio) showed PS, PDI, ZP, and EE% values of 312.9 ± 3.617 nm, 0.157 ± 0.014, −17.0 ± 0.513 mV, and 86.54 ± 1.818%, respectively. The optimised AA-SLNs (1:2 drug-to-lipid: ratio) had a PS of 115.5 ± 0.458 nm, PDI of 0.255 ± 0.007, ZP of −11.9 ± 0.321 mV, and EE% of 76.22 ± 0.436%. The SLNs remained stable for 60 days at 4 °C and room temperature (p < 0.05). The solubility study revealed that free OA and AA showed no measurable values in the three solvents. However, OA-SLNs showed the highest solubility in H₂O (16-fold) followed by PBS at pH 6.8 (10-fold) and pH 1.2 (10-fold). AA-SLNs significantly improved the solubility in PBS at pH 6.8 (88-fold), compared to dH₂O (6-fold) and PBS at pH 1.2 (26-fold). In vitro drug release studies showed that OA release from the SLNs was significantly increased within 300 min (p < 0.05) compared to the free drug. Similarly, AA release from the SLNs was significantly increased within 300 min (p < 0.05) compared to free AA. Conclusions: These results demonstrate that SLNs enhance OA and AA solubility and drug release, suggesting a promising strategy for improving oral bioavailability and therapeutic efficacy. Full article

Poloxamer-based drug delivery systems are widely used in the pharmaceutical sector. The structural characterization of these systems is crucial for the development of new drug delivery systems and for the optimization of their properties. In this study, we utilized small-angle neutron scattering (SANS) to investigate the structures of poloxamer-based drug delivery systems. The samples were measured using the SANS technique on the VSANS-V16 instrument at Helmholtz-Zentrum Berlin (HZB), Germany. The samples contained 20% poloxamer (P407) and 0.2% of a drug (ibuprofen, ketoprofen, diclofenac) in deuterated water (D₂O) for SANS. The samples varied in terms of temperature analysis (25 °C, common storage temperature; 37 °C, human body temperature; 40 °C, fever temperature). The data analysis involved modeling the data using a Python-based routine. The model used consisted of an isotropic solution of polydisperse spherical micelles. The intensity as a function of the scattering vector was modeled as the product of the form factor and the interparticle structure factor, with the latter described within the local monodisperse approximation regime. Additionally, a scattering contribution was observed, which was associated with the presence of crystalline superstructures formed by micelles that organized into a cubic structure. The data analysis provided important information about the system, such as the average radius, the size distribution, and the thickness of the layer surrounding the micellar core. The results will contribute to the development and optimization of new drug delivery systems that are more effective and safer for medical applications. Full article

SARS-CoV-2 can cause neurological issues, including cognitive dysfunction in COVID-19 survivors. Endothelial dysfunction, a key mechanism in COVID-19, is also a risk factor for vascular dementia (VaD). Reduced nitric oxide (NO) bioavailability is a pathogenic factor of endothelial dysfunction and platelet aggregation in COVID-19 patients, and endothelial NO synthase (eNOS) levels decline with advancing age, a risk factor for both COVID-19 morbidity and VaD. SARS-CoV-2 also induces cellular senescence and senescence-associated secretory phenotype (SASP). We hypothesized that eNOS deficiency would worsen neuroinflammation, senescence, blood–brain barrier (BBB) permeability, and hypercoagulability in eNOS-deficient mice. Six-month-old eNOS^+/− (pre-cognitively impaired experimental VaD) and wild-type (WT) male mice were infected with mouse-adapted (MA10) SARS-CoV-2. Mice were evaluated for weight loss, viral load, and markers of inflammation and senescence 3 days post-infection. eNOS^+/− mice showed more weight loss (~15%) compared to WT mice (~5%) and increased inflammatory markers (Ccl2, Cxcl9, Cxcl10, IL-1β, and IL-6) and senescence markers (p53 and p21). They also exhibited higher microglial activation (Iba1) and increased plasma coagulation and BBB permeability, despite comparable lung viral loads and absence of virus in the brain. This is the first experimental evidence demonstrating that eNOS deficiency exacerbates SARS-CoV-2-induced morbidity, neuroinflammation, and brain senescence, linking eNOS to COVID-19-related neuropathology. Full article